Compositions and methods for controlling pest insects

ABSTRACT

Compositions of a purine, a xanthine oxidase inhibitor and/or a dihydrofolate reductase inhibitor, and methods of using same, for controlling the growth of pest insects which salvage, store, or excrete their nitrogenous wastes via the purine metabolic pathway.

This is a division of application Ser. No. 08/457,705, filed Jun. 1,1995, now U.S. Pat. No. 5,620,982, which is a division of applicationSer. No. 08/291,072, filed Aug. 17, 1994, now U.S. Pat. No. 5,514,681,issued May 7, 1996.

BACKGROUND OF INVENTION

1. Field of the Invention

The present invention is directed to the regulation of the growth ofpest insects which utilize the purine metabolic pathway to salvage,store, or excrete their nitrogenous wastes. It comprises bringing intocontact with the pest insects, formulations containinggrowth-controlling amounts of compositions comprising purines, purinemetabolic-enzyme inhibitors, and inhibitors of enzymes which regulateproduction of specific co-factors of this pathway.

2. Description of the Background Art

Despite the recent development and great promise of such advancedinsect-controlling techniques as chemical sterilants, pheromones, andecologically-based control strategies, the use of chemical insecticidesstill plays a predominant role. However, rising public awareness ofenvironmental issues, more stringent government regulations, andincreasing insect resistance to conventional modalities are driving thepest control industry to seek safer alternatives to these conventionalchemical insecticides.

Others have attempted to identify and evaluate the efficacy of insectgrowth inhibitors. However, given the continuous need for increasedselectivity and effectiveness of insect control agents, it becamedesirable to engage in rational formulation of control agents based onan understanding of key insect nutritional and metabolic pathways.

SUMMARY OF THE INVENTION

It is widely acknowledged that the majority of insects are uricotelic inthat they excrete their excess nitrogen as uric acid and uricolyticderivatives thereof (Cochran (1975), "Excretion in Insects" in InsectBiochemistry and Function pp. 171-281). The uric acid is synthesized,via the purine catabolic pathway shown in FIG. 1, and is either excretedto the outside, or, in some cases, stored by the insect as a metabolicreserve.

Cockroaches are a good model of the essential nature ofstorage-excretion of uric acid. For example, in German cockroaches, aslurry of uric acid is passed to the female during mating, as a paternalinvestment. The female, in turn, invests the developing eggs with asupply of uric acid that is used during embryogenesis (Mullins & Keil(1980), Nature 283: 567-569). Interruption of this vital cycle appearshighly detrimental to cockroach population growth, which depends heavilyon these uric acid stores (Engebretson & Mullins (1986), Comp. Biochem.Physiol. 83B: 93-97; Suiter et al. (1992), J. Econ. Entomol. 85(1):117-122). In the cockroach fat body, de novo synthesis of uric acidtakes place, largely through purine salvage, in the trophocytes and theuric acid is stored in specialized urocytes for recycling (Cochran(1985), Ann. Rev. Entomol. 30: 29-49). This is accomplished throughuricolytic digestion of the stored urates by endosymbiont bacteria whichare sequestered in bacteriocyte cells adjacent to the urocytes (Wren &Cochran (1987), Comp. Biochem. Physiol. 88B: 1023-1026). In this part ofthe uric acid cycle, the endosymbiont bacteria use xanthinedehydrogenase to reduce the urates to xanthine, and disruption of anypart of this system also inhibits population growth.

Another essential facet of insect physiology is the molt cycle, when thecuticular epithelial cells multiply and synthesize a new, largerexoskeleton just prior to ecdysis (Chapman (1982), The Insects Structureand Function. Cambridge, Mass.: Harvard University Press; Hepburn(1985), "The Integument" in Fundamentals of Insect Physiology. Ed. M. S.Blum, pp. 139-183. New York: John Wiley & Sons, Inc.). At the same time,many of the internal tissues are growing, as in cockroaches where, forexample, development of the internal and external reproductive organsprogresses with each stage, culminating at the final molt to thesexually mature adult (Chapman (1982) The Insects Structure andFunction, Cambridge Mass.: Harvard University Press). During thisprocess, insects draw heavily on their metabolic reserves to achieve therapid growth of cells which takes place.

The purine metabolic pathway is central to all of these processes, and,thus, to homeostasis of insects. As in any of the known biochemicalpathways, the hydrolytic enzymes and their co-factors are essential tothe functioning of the purine degradative pathway. This pathway alsoserves to salvage the free purine bases for re-use in nucleotide andnucleic acid biosynthesis (Lehninger (1970) Biochemistry: The MolecularBasis of Cell Structure and Function. 2nd Ed. pp. 740-742).

Two of the enzymes involved in this pathway are xanthine oxidase anddihydrofolate reductase (also known as tetrahydrofolate dehydrogenase).Xanthine oxidase (E.C. 1.2.3.2), a molybdenum iron sulfur flavo-enzyme,functions late in the salvage pathway of purine catabolism fromguanosine monophosphate and inosine monophosphate to xanthine, andfinally, to uric acid. In this pathway, xanthine oxidase catalyzes boththe conversion of hypoxanthine to xanthine, and the conversion ofxanthine to uric acid (Coughlan (1980) Molybdenum andMolybdenum-Containing Enzymes. New York: Pergamon Press). Functioning asxanthine dehydrogenase, the same enzyme reduces uric acid to xanthine inthe uricolytic pathway of the endosymbiont bacteria in the cockroach fatbody (Wren & Cochran (1987), Comp. Biochem. Physiol. 88B: 1023-1026).Dihydrofolate reductase catalyzes the synthesis of tetrahydrofolate,which is an essential co-factor in the uric acid and purine synthesispathways (Kucers & Bennett (1979), "Trimethoprim and Cotrimoxazole" inThe Use of Antibiotics. 3rd Ed. London: William Heinemann Medical Books,Ltd.).

An understanding of these insect systems, which rely on the recyclingand excretion of their purines, led to the present invention, whichprovides novel compositions and methods for disrupting insecthomeostasis and inhibiting insect population growth. Thus, in oneembodiment, these compositions comprise (1) a purine such as guanine(2-amino-1,7-dihydro-6H-purin-6-one); hypoxanthine(1,7-dihydro-6H-purin-6-one); or xanthine(3,7-dihydro-1H-purine-2,6-dione), and mixtures thereof, and (2) axanthine oxidase inhibitor, preferably one of the 6-unsubstitutedpyrazolo 3,4-d!pyrimidine group, such as oxypurinol(4,6-dihydroxypyrazolo 3,4-d!pyrimidine); 4-mercapto-6-hydroxypyrazolo3,4-d!pyrimidine; 4,6-dimercaptopyrazolo 3,4-d!pyrimidine,4-amino-6-hydroxypyrazolo 3,4-d!pyrimidine; 4-hydroxy-6-mercapto3,4-d!pyrimidine; or allopurinol (4-hydroxypyrazolo 3,4-d!pyrimidine),and mixtures thereof. In another embodiment, these compositions comprise(1) a purine; (2) a xanthine oxidase inhibitor; and (3) a dihydrofolatereductase inhibitor such as trimethoprim(2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine), methotrexate (N- 4-(2,4-diamino-6-pteridinyl)methyl!methylamino!benzoyl!-L-glutamic acid),or pyrimethamine (5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine), andmixtures thereof.

While specific purines in combination with specific enzyme inhibitorsare utilized to illustrate the present invention, it is understood thatany of the purines and inhibitors of any of the enzymes of the pathwayof FIG. 1 may be applied according to the present invention.

Furthermore, while the cockroach is utilized to illustrate the presentinvention, it is understood that the compositions and methods of thepresent invention may be applied to regulate the growth of any pestinsect which utilizes the purine metabolic pathway to salvage, store, orexcrete to the outside, its nitrogen wastes.

A further embodiment of the invention comprises an insect bait orattractant formulation containing an insect-growth-regulating effectiveamount of the compositions.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the pathway for purine catabolism.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated on the discovery that ingestion offormulations containing growth controlling amounts of certain novelcompositions by pest insects, particularly cockroaches, disruptshomeostasis and inhibits population growth.

The compositions of the present invention may be the sole activeingredients of the formulation or they may be admixed with one or moreadditional active ingredients, such as other, conventional insecticides.

The compositions of the present invention may be formulated with a"bait" or "attractant." For purposes of description of the presentinvention, these terms refer to any formulation to which pest insectsare attracted and which they will ingest. Such compositions arewell-known to those skilled in the art and it will be understood thatany such material which is inert with respect to the compositions of thepresent invention may be employed in the practice of the invention.

In use, the formulations may be applied to the pest insects, to thelocus of the pest insects, and/or to the habitat of the pest insects.

The following examples are included for purposes of illustration onlyand are not intended to be limiting, unless otherwise specified.

EXAMPLE 1 General Procedure

German cockroaches (Blatella germanica L.) from the stock laboratory"VPI" strain were used to form experimental colonies of mixed lifestages. Unless otherwise specified, each insect colony of 42 insectscontained five each of newly post-emergent adult males and females,eight each of male and female nymphs at the fifth nymphal stage, andeight each of male and female nymphs at the third nymphal stage. Carewas taken to select insects from the same stock colonies for eachexperimental block, and each colony was allowed to acclimatize fortwenty-four (24) hours prior to treatment.

The colonies were housed in one-gallon glass battery jars fitted withfiber-board platforms, with clean tap-water offered continuously incotton-stoppered glass vials. The jars were rimmed with a thin coatingof petrolatum, and covered closely with three layers of cheesecloth heldin place with strong elastic bands. These measures prevented escape ofthe test insects, as well as contamination by other insects.

Each test included "control" colonies, in which the food was untreated,and "test" colonies, in which the food was mixed with the compositionsbeing tested to form percent concentrations by weight (w/w). Unlessotherwise specified, the food was Agway Laboratory Rat Chow and wasprepared by grinding the chow pellets to a fine powder and, for testcolonies, incorporating the test compounds by grinding and mixing themwith the chow, using a mortar and pestle. Food, either treated oruntreated, was pre-weighed in stainless steel planchettes and offeredwith the planchettes placed in plastic cups, to avoid loss throughspillage. During tests, the planchettes were weighed weekly and foodreplenished when necessary.

Replicate colonies were initiated on consecutive days, with all colonieshoused in the stock laboratory under the same conditions of ambienttemperature (25° C.), and humidity as during rearing. A control "blankcolony", which was identical to a control colony except that no insectswere included, was monitored for loss or gain of moisture in the fooddue to changes in ambient humidity. Any such changes were factored intothe calculations of food consumption.

A record was kept of all dead insects, which were counted and sexedweekly when the food was weighed. Dead insects were frozen and stored at-4° C. prior to being subjected to a whole-body uric acid assay. Unlessotherwise specified, the total population of each colony was countedevery three (3) weeks. When all of the insects, or all of the females,were dead or moribund, the colony was determined to be non-viable andthe experiment was terminated. Remaining insects were killed by freezingand stored frozen, as above, to await assaying for uric acid.

The mean percent change (Δ%) in population number for each colony wascalculated, with the initial number (42) representing 100%. Foodconsumption, in milligrams per individual cockroach (ICmg), wascalculated for the first three (3) weeks of the experiment, prior tonymphs hatching. These measurements determined whether the testcompositions were ingested, and whether such compositions were effectivein inhibiting population growth.

EXAMPLE 2 Uric Acid Assay

Determination of the whole-body uric acid content of the deadcockroaches was conducted essentially according to a standard uricaseassay (Cochran (1973) Comp. Biochem. Physiol. A46: 409-419). Individualcockroaches, with wings and legs trimmed off, were dried for 24-48 hoursat 60° C., weighed, and ground to a fine powder. Uric acid was extractedfrom the dry tissue with 0.6% aqueous lithium carbonate for three (3)hours at 60° C. with continuous shaking. The extracts were centrifugedto remove tissue debris. After mixing with uricase, the maximumabsorption at 292 nm was determined spectrophotometrically, and uricacid concentration was calculated in μg uric acid/mg of dry tissue.

EXAMPLE 3 Assessment of Xanthine Food Compositions

In two experiments (3a) and (3b), the effects of adding 1% xanthineSigma Chemical Co.! to the basic cockroach diet of ground rat chow, werestudied. The colonies in each experiment were set up as described inExample I, with the diets being either rat chow alone (RC), or ratchow+1% xanthine (RCX). Each experiment included three replicatecolonies for each condition (n=3).

The populations were counted at 6 and 9 weeks (3a) or 10 and 12 weeks(3b), and the percent change in mean population numbers (Δ%) wascalculated. Individual consumption (ICmg) of the diets for the firstthree weeks of treatment was calculated from the food-weight data.

The results are shown in Table 1. The addition of xanthine appearedneither to inhibit feeding nor to adversely affect population growth. Infact, xanthine appeared to enhance reproduction, as population numberswere higher in xanthine-treated colonies than in those fed rat chowalone.

                                      TABLE 1                                     __________________________________________________________________________    EXPERIMENT 3a        EXPERIMENT 3b                                                 ICmg            ICmg                                                     TIME (±SEM)                                                                             Δ%(*)                                                                           (±SEM)                                                                             Δ%                                         (wk) RC  RCX RC  RCX RC  RCX RC  RCX                                          __________________________________________________________________________    3    55.8                                                                              55.3        58.0                                                                              57.9                                                      (±0.9)                                                                         (±2.7)   (±0.4)                                                                         (±0.8)                                            6            +224%                                                                             +278%                                                        9            +707%                                                                             +921%                                                        10                           +1405%                                                                            +1433%                                       12                           +1774%                                                                            +1869%                                       __________________________________________________________________________     (*) + = increase                                                              Table 1: Mean individual consumption (ICmg) and percent change (Δ%)     in mean population number over time (weeks), in colonies of German            cockroaches administered offered food without (RC) or with 1% xanthine        (RCX). n = 3                                                             

EXAMPLE 4 Assessment of Xanthine-Oxypurinol Compositions

Colonies of German cockroaches were prepared as described. The dietsadministered were rat chow alone (RC); rat chow with oxypurinol SigmaChemical Co.! (RC+OXY%); and rat chow with 1% xanthine (RCX) and withoxypurinol (+OXY%) at five concentrations (w/w). Individual consumption(ICmg), population growth control, and whole-body uric acidconcentrations were determined.

Individual consumption (ICmg) in the first three weeks was calculated,and the results shown in Table 2a below. The addition of oxypurinolalone caused a decrease in food consumption over controls fed untreatedfood. The addition of xanthine to the diet caused the consumption ofoxypurinol-treated food to increase by 35% at 0.1% oxypurinolconcentration, and by 56% at the 1.0% oxypurinol concentration.

                                      TABLE 2a                                    __________________________________________________________________________    XANTHINE 0%     XANTHINE 1%                                                   TIME     RC + OXY %                                                                           RC + OXY %                                                    (wk) RC  0.1                                                                              1.0 0.1 0.5 1.0  2.0 3.0                                          __________________________________________________________________________    3    53.7                                                                              36 32  48.5                                                                              58.3                                                                              49.9 52.6                                                                              45.6                                              (*2.0)     (*1.4)                                                                            (*0.8)                                                                            (*1.9)                                                                             (*1.5)                                                n = 9*                                                                            n = 1                                                                            n = 1                                                                             n = 6                                                                             n = 3                                                                             n = 6                                                                              n = 6                                                                             n = 1                                        __________________________________________________________________________     * = number of colonies                                                        Table 2a: Mean individual consumption (ICmg) of rat chow over three weeks     with or without 1% xanthine, and with various concentrations (w/w) of         oxypurinol (OXY %).                                                      

The percent change (Δ%) in mean colony population numbers at 5.5, 6, 7,9, 10 and 12 weeks of treatment were determined as described, with theresults shown in Table 2b below. The addition of oxypurinol alone to thediet did not inhibit population growth. The addition of xanthine plusoxypurinol inhibited population growth to the point of extinction.

                                      TABLE 2b                                    __________________________________________________________________________    XANTHINE 0%        XANTHINE 1%                                                TIME RC    RC + OXY %                                                                            RC + OXY %                                                 (wks)                                                                              CONTROL                                                                             0.1 1.0 0.1 0.5                                                                              1.0 2.0 3.0                                         __________________________________________________________________________    5.5  +690% +460%                                                                             +1060%                                                              n = 1 n = 1                                                                             n = 1                                                          6    +126%         -31%                                                                              -50%                                                                              -5%                                                                              -11%                                                                              -55%                                             n = 5                                                                    9    +812%         -92%                                                                              -92%                                                                             -64%                                                                              -77%                                                                              -88%                                             n = 5                                                                    7    +719%         -64%   -75%                                                                              -69%                                            10   +1405%        -91%   -98%                                                                              -98%                                            12   +1774%        -94%   -100%                                                                             -100%                                           __________________________________________________________________________     Table 2b: Percent changes (+ or - Δ%) in mean population number, in     colonies of German cockroaches offered food with or without 1% xanthine,      and with various concentrations (w/w) of oxypurinol (OXY %), over time        (weeks). Except where noted, n = 3.                                      

Whole-body uric acid concentrations were calculated from standarduricase assays for cockroaches that died during weeks 5-9 of treatment.Samples from the VPI laboratory strain of German cockroaches also wereassayed to show typical "base-line" levels of urates before treatment.

As shown in Table 2c below, females in the VPI strain typically exhibita slightly higher uric acid level than males, regardless of stage.However, as shown in Tables 2d-2f below, after several weeks of feedingwith xanthine and oxypurinol in the diet, there is a marked decline inwhole-body urate concentration in all groups regardless of age or sex.

                  TABLE 2c                                                        ______________________________________                                                              AGE    URIC ACID                                        STAGE    GENDER       (wks)  μg/mg ± SEM                                ______________________________________                                        adult    males        6-7    1.80                                                      n = 9               ±0.12                                                  females             2.41                                                      n = 10              ±0.06                                         nymph    males        5-6    2.34                                                      n = 10              ±0.10                                                  females             2.44                                                      n = 10              ±0.22                                         nymph    males        3-4    0.77                                                      n = 10              ±0.10                                                  females             1.51                                                      n = 10              ±0.10p                                        ______________________________________                                         Table 2c: Mean, wholebody uric acid concentrations (μg/mg of 25 dry        tissue weight, ±SEM), in different age and gender groups of the VPI        laboratory strain of German cockroaches that are typical of those used in     the feeding experiments.                                                 

                  TABLE 2d                                                        ______________________________________                                        TIME               RCX + OXY %                                                (wks)      RC      0.1        1.0   2.0                                       ______________________________________                                        5          2.42    0.54       0.32  0.31                                                 ±0.12                                                                              ±0.05   ±0.06                                                                            ±0.05                                             n = 5   n = 25     n = 17                                                                              n = 17                                    6          2.79    0.43       0.30  0.27                                                 ±0.21                                                                              ±0.04   ±0.04                                                                            ±0.03                                             n = 4   n = 32     n = 35                                                                              n = 26                                    7          2.78    0.54       0.25  0.21                                                 ±0.25                                                                              ±0.10   ±0.04                                                                            ±0.04                                             n = 6   n = 8      n = 14                                                                              n = 12                                    9          3.16    0.51       0.14  0.32                                                 ±0.06           ±0.04                                                                            ±0.10                                             n = 10  n = 1      n = 7 n = 3                                     ______________________________________                                         TABLE 2d: Mean wholebody uric acid concentrations (μg/mg dry tissue        weight ±SEM) in male German cockroaches on food without (RC), or with      1% xanthine (RCX) and various percent concentrations (w/w) of oxypurinol      (OXY %).                                                                 

                  TABLE 2e                                                        ______________________________________                                        TIME             RCX + OXY %                                                  (wks)     RC     0.1         1.0   2.0                                        ______________________________________                                        5         2.63   0.31        0.31  0.28                                                 ±0.14                                                                             ±0.13    ±0.04                                                                            ±0.08                                             n = 3  n = 6       n = 8 n = 7                                      6         3.13   0.31        0.34  0.35                                                 ±0.04                                                                             ±0.03    ±0.06                                                                            ±0.06                                             n = 4  n = 27      n = 27                                                                              n = 18                                     7         2.95   0.43        0.22  0.26                                                 ±0.18                                                                             ±0.04    ±0.04                                                                            ±0.06                                             n = 4  n = 24      n = 23                                                                              n = 14                                     9         3.14   0.21        0.29  0.34                                                        ±0.03    ±0.04                                                                            ±0.05                                             n = 1  n = 21      n = 14                                                                              n = 13                                     ______________________________________                                         Table 2e: Mean wholebody uric acid concentrations (μg/mg dry tissue        weight ±SEM) in female German cockroaches on food without (RC) or with     1% xanthine (RCX) and various percent concentrations (w/w) of oxypurinol      (OXY).                                                                   

                  TABLE 2f                                                        ______________________________________                                        TIME             RCX + OXY %                                                  (wks)    RC      0.1         1.0   2.0                                        ______________________________________                                        5        1.95    0.53        0.32                                                      ±0.36                                                                              ±0.04    ±0.18                                                  n = 4   n = 3       n = 2                                            6        2.95                      0.08                                                ±0.09                  ±0.06                                            n = 5                     n = 2                                      7        3.14                      0.13                                                ±0.03                  ±0.08                                            n = 4                     n = 2                                      9        3.26                      0.14                                                n = 1                     n = 1                                      ______________________________________                                         Table 2f: Mean wholebody uric acid concentrations (μg/mg dry tissue        weight ±SEM) in German cockroach nymphs offered food without (RC), or      with 1% xanthine (RCX) and various percent concentrations (w/w) of            oxypurinol (OXY).                                                        

EXAMPLE 5 Assessment of Xanthine-Oxypurinol Compositions Offered forDifferent Durations

Colonies were prepared as described. The food was treated with 1%xanthine and various concentrations of oxypurinol, and was offered fordurations of either 24 hours, or 1, 2, or 3 weeks. At the end of thetreatment time, the treated food was removed, and the insects wereoffered untreated rat chow for the remainder of the test time.

As shown in Table 3 below, the data indicates that a minimum dose ofoxypurinol must be ingested over time to achieve population inhibition.For example, the 24-hour treatment affected population numbers whencompared with the control, but did not control population numbers at anyconcentration of oxypurinol. Calculation revealed that the individualconsumption of oxypurinol ingested during this time ranged from 6-104μg.

                  TABLE 3                                                         ______________________________________                                        Percent change (+ or -) in mean population numbers in                         colonies fed a diet of rat chow alone (RC), or rat chow                       combined with 1% xanthine (RCX), and with various                             concentrations. (w/w) of oxypurinol (OXY %). Duration of                      treatments was 24 hrs, or 1, 2, or 3 weeks, after which rat chow              alone was offered. n = 3.                                                     TREATMENT                                                                              TIME              RCX + OXY %                                        DURATION (wks)    RC       0.1    1.0   2.0                                   ______________________________________                                        2.4 hours                                                                              6        +500%    +250%  +114% +109%                                 1 week   6        +887%    +137%  -45%  -49%                                           9        +1157%   +320%  -63%  -57%                                           12       +1560%   +853%  -5%   -31%                                  2 weeks  9        +591%    +36%   -65%  -90%                                           12       +750%    +213%  -66%  -94%                                           15       >+750%   +561%  -45%  -96%                                  3 weeks  6        +391%     -58%  -71%  -92%                                           9        +1050%    -71%  -92%  -97%                                           12       +1604%    -79%  -96%  -98%                                  ______________________________________                                    

Treatment with 0.1% oxypurinol for one or two weeks also resulted inlower population numbers when compared with controls, and delayedegg-hatch by 1-2 weeks, but the treated colonies were recovering whenthey were terminated at 12 weeks. However, three (3) weeks of treatmentat 0.1% oxypurinol did cause a substantial reduction in populationnumbers in the weeks following treatment, with no recovery noted by 12weeks, and with only one viable eggcase, which hatched six weeks laterthan normal.

Colonies treated for two (2) weeks with 2% oxypurinol, or for three (3)weeks with 1% or 2% oxypurinol did not recover, even when the "recovery"time was extended to fifteen (15) weeks. Mean individual consumption ofoxypurinol was 734 μg, 579 μg, and 1,140 μg respectively.

EXAMPLE 6 Assessment of Food Choice

Colonies were prepared as described, with three replicates of eachcondition. Planchettes containing either untreated food (RC) or foodtreated with xanthine+oxypurinol (RCX+0%) were offered together in eachcolony. Food weights for each planchette were calculated to determinehow much of each was consumed. The treatments consisted of rat chow with1% xanthine and oxypurinol at either 0.1%, 0.5% or 1.0% (w/w)concentration. The control colony was given two planchettes of untreatedrat chow.

The results, as shown in Table 4 below, indicate that the insectsconsumed either the same quantity of treated and untreated food (at 0.5%oxypurinol), or ate more of the treated than the untreated food (at 0.1%and 2.0% oxypurinol). The range of oxypurinol ingested was calculated tobe between 29 μg and 265 μg per individual over the first three weeks,and a high level of population-growth control was achieved, especiallyat 1.0% oxypurinol concentration.

                                      TABLE 4                                     __________________________________________________________________________    Individual consumption (ICmg) and percent change in                           mean population numbers (Δ%) over time (wks), in colonies where         treated (RCX ± 0%) and untreated (RC) food were offered together           as a choice of diet. The amount of oxypurinol ingested over                   the first three weeks is shown as μg/individual (IC μg OXY), and        the ratio of treated and untreated food consumed is given as a                percent of the total amount eaten (% TOTAL).                                  TIME     RC       RCX + 0% RCX + 0% RCX + 0%                                  (wks)                                                                             TEST CONTROL                                                                             RC 0.1   RC 0.5   RC 1.0                                       __________________________________________________________________________    3   ICmg 58.9  23.1                                                                             29.4  25.7                                                                             25.6  24.7                                                                             26.5                                          ±SEM                                                                            ±1.7                                                                             ±3.1                                                                          ±0.3                                                                             ±1.O                                                                          ±1.3                                                                             ±0.9                                                                          ±2.O                                       IC μg                                                                           0     0  29.4  0  128   0  265                                           OXY                                                                           % TOTAL                                                                            100%  43%                                                                              57%   50%                                                                              5O%   48%                                                                              52%                                       7   Δ%                                                                            +422%                                                                              -64%                                                                             -72%                                                        9   Δ%                                                                           +1378%                                                                              -71%                                                                             -80%  -94%                                                  12  Δ%                                                                           +2007%                                                                              -76%                                                                             -71%  -96%                                                  __________________________________________________________________________

EXAMPLE 7 Life Stage Effects of Xanthine-Oxypurinol Compositions

Colonies of German cockroaches were housed as reviously described, withthe usually mixed stages separated into three different colonies.Colonies consisted of either newly-molted adults (five males and fivefemales, 6-7 weeks old); large nymphs (eight males and eight females,5-6 weeks old); or small nymphs (eight males and eight females, 3-4 eeksold). Colonies of older adults (five males and five females, 7-8 weeksold) also were tested.

Colonies were fed untreated rat chow (RC), or rat chow treated with 1%xanthine (RCX) plus various levels (w/w) of oxypurinol (OXY%).Individual consumption (ICmg) and percent change in mean populationnumber (Δ%) were determined for each stage, and are shown in Tables 5athrough 5d below, for adults, large nymphs, small nymphs, and olderadults, respectively.

The data in these tables confirm that the primary impact of treatmentwith xanthine plus oxypurinol occurs as the cockroaches attempt toreproduce. The effect is probably caused by depletion of the insects'metabolic reserves, including uric acid stores which cannot be replacedbecause of irreversible enzyme inhibition. However, very small nymphsgowhich hatch in a dying colony also are affected in that they areusually too weak to survive, and rarely reach their second instar. It isprobable that they are not invested with the metabolic reserves that arenormally passed to them prenatally. Their continued feeding on treatedfood also prevents the young nymphs from developing their own metabolicstores, especially stores of uric acid.

Adult males were observed to be the first to die. At mating, adult malesutilize a large part of their reserves to pass urates as well as maturesperm to the females. Females who have just produced an egg-case, whichnecessitates a large investment of nutritional reserves, die shortlythereafter, usually with the non-viable egg-case protruding from theovipositor.

Cochran observed that cyclic feeding occurs in adult females in relationto egg production (Cochran (1983) Entomol. Exp. Appl. 34: 51-57). Inthis oothecal cycle, the females feed vigorously while maturing theoocytes, and sparingly while carrying an egg-case. These phenomena wouldaccount for the high feeding rates and early mortality of thenewly-emerged adults (Table 5a), as well as the low feeding rates of theolder adults (Table 5d). These latter females were likely to alreadyhave matured the eggs that would fill oothecae soon after the colony wasassembled, and thus were in the low feeding-rate part of their cycle.Their first nymphal hatch would account for the precipitous rise inpopulation numbers in these colonies (Table 5d), followed by the gradualweakening of the colonies as the adults attempted to reproduce furtherand the newly-hatched nymphs died.

Nymphs followed the same pattern of mortality as the adults, and weremost affected by the treated diet after molting to the adult stage, whenthey normally feed vigorously in preparation for maturing their firstoocytes. The delay in the rate at which the population declined in thelarge nymph colony (Table 5b), and small nymph colony (Table 5c), isfurther evidence that the major impact occurs during reproduction. Thiswould have happened between weeks 9-11 of the experiment for theseage-groups.

The effective dosage range for oxypurinol with xanthine is very wide inthese experiments, causing high mortality at 99.5 μg/individual measuredover three weeks in the newly-molted adults (Table 5a), and slowercontrol at higher individual consumption rates when the colonies werestarted as nymphs. However, it is clear that, although there is adifferent effect on the cockroaches depending on their age whentreatment is started, they are all affected as they attempt toreproduce.

                  TABLE 5a                                                        ______________________________________                                        Individual consumption (ICmg) and percent change in                           mean population number (Δ%) in colonies of newly-molted adult           German cockroaches fed untreated rat chow (RC) or rat chow                    treated with 1% xanthine (RCX) and various Concentrations (w/w)               of oxypurinol (OXY %).                                                        COLONY STARTED AS ADULTS (n = 1)                                              TIME                      RCX + OXY %                                         wks   TEST       RC       0.1    1.0   2.0                                    ______________________________________                                        3     ICmg       87.0     99.5   76.8  84.8                                   3     IC μg OXY                                                                             0        99.5   768   1696                                   6     Δ%   +1430%    -94%  -75%   -88%                                  9     Δ%   +1310%   -100%  -90%  -100%                                  12    Δ%   +1810%   -100%  -100% -100%                                  ______________________________________                                    

                  TABLE 5b                                                        ______________________________________                                        Individual consumption (ICmg) and percent change in                           mean population number (66 %) in colonies of large German                     cockroach nymphs (5-6 weeks old at the starting date) fed                     untreated rat chow (RC) or rat chow treated with 1% xanthine                  (RCX) and various concentrations (w/w) of oxypurinol (OXY %).                 COLONY STARTED AS LARGE NYMPHS (n = 1)                                        TIME                      RCX + OXY %                                         wks   TEST       RC       0.1    1.0   2.0                                    ______________________________________                                        3     ICmg       82.8     76.9   65.3  79.3                                   3     IC μg OXY                                                                             0        76.9   653   1586                                   6     Δ%     -6%    -50%   -31%   -6%                                   9     Δ%   +1613%   -69%   -81%   -63%                                  12    Δ%   +1800%   -88%   -100% -100%                                  ______________________________________                                    

                  TABLE 5c                                                        ______________________________________                                        Individual consumption (ICmg) and percent change in                           mean population number (Δ%) of small German cockroach nymphs            (3-4 weeks old at the starting date) fed untreated rat chow                   (RC) or rat chow treated with 1% xanthine (RCX) and various                   concentrations (w/w) of oxypurinol (OXY %).                                   COLONY STARTED AS SMALL RYMPHS (n = 1)                                        TIME                      RCX + OXY %                                         wks   TEST        RC      0.1    1.0    2.0                                   ______________________________________                                        3     ICmg        54.9    53.9   52.4   40.4                                  3     Ic μg OXY                                                                              0       53.9   524    808                                   6     Δ%     -50%   -31%   -19%   -81%                                  9     Δ%    +719%   -69%   -81%   -88%                                  12    Δ%    +775%   -88%   -100%11                                                                              -100%                                 ______________________________________                                    

                  TABLE 5d                                                        ______________________________________                                        Mean individual consumption (ICmg) and percent change                         in mean population number (Δ%) in colonies of older German              cockroach adults (8-9 weeks old at the starting date) fed                     untreated rat chow (RC) or rat chow treated with 1% xanthine                  (RCX) and various concentrations (w/w) of oxypurinol (OXY%).                  COLONY STARTED AS OLDER ADULTS (n = 3)                                        TIME                      RCX + OXY %                                         wks   TEST       RC       0.1    1.0   2.0                                    ______________________________________                                        3     ICmg       38.7     37.2   35.0  35.2                                         ±SEM             ±1.9                                                                              ±0.6                                                                             ±1.8                                3     ICpg OXY   0        37.2   350   704                                    6     Δ%   +1150%   +557%  +403% +823%                                  9     Δ%   +1030%   +33%   +40%  +197%                                  12    Δ%   +1820%   -73%   -67%   -30%                                  ______________________________________                                    

EXAMPLE 8 Assessment of Compositions Containing Trimethoprim

Replicate colonies of German cockroaches were prepared as described. Thediets administered were either rat chow alone (RC); rat chow withvarious concentrations of trimethoprim (RC+T%) (w/w), or rat chow with1% xanthine (RCX) and various concentrations (w/w) of trimethoprim (T%).

As shown in Table 6a below, the addition of trimethoprim alone did notinhibit population growth, although there was some eventual weakening ofthe treated colonies. As shown in Table 6b below, however, thecombination of xanthine and trimethoprim caused rapid inhibition ofpopulation growth.

Whole-body uric acid concentrations were calculated from standarduricase assays, as previously described. As shown in Table 6c below,uric acid metabolism was not affected by treatment with a combination ofxanthine and trimethoprim.

During the first three-weeks, there was a mean Δ% of -82% of thepopulations in the treated colonies, with 65% of these still nymphs whenthey died. This represents 72% of the nymphs used for the experiment,and confirms that effects are most pronounced during nymphal molt.

                  TABLE 6a                                                        ______________________________________                                        Mean individual consumption (ICmg) of rat chow                                without (RC) or with various concentrations (w/w) of                          trimethoprim (RC + T%), qver time (weeks), shown in conjunction               with percent change in mean population number (Δ%), in colonies         of German cockroaches where the starting number (42) = 100%.                  n = 5                                                                         TIME                 RC + T%                                                  WKS   TEST      RC       0.5     1.0    2.0                                   ______________________________________                                        3     ICmg      62       61      58     54                                          ±SEM   ±2.2  ±3.5 ±3.4                                                                              ±1.7                               12    Δ%  +1398%   +1246%  +1013% +384%                                 ______________________________________                                    

                  TABLE 6b                                                        ______________________________________                                        Mean individual consumption (ICmg), and percent                               change in mean population number (Δ%), over time (weeks), in            colonies of German cockroaches offered food without (RC), or                  with (RCX) 1% zanthine and various concentrations (w/w) of                    trimethoprim (T %), where the colony starting number (42) =                   100%.                                                                                        RCX + T %                                                      TIME             RC      1.0     2.0   3.0                                    wks   TEST       n = 6   n = 3   n = 12                                                                              n =  3                                 ______________________________________                                        1     ICmg       17.3    12.0     8.8   5.8                                         ±SEM    ±2.4 ±0.9 ±0.7                                                                             ±0.1                                      Δ%   -1%     -4%     -28%  -41%                                   3     ICmg       44.7    33.9    22.6  13.4                                         ±SEM    ±2.1 ±1.1 ±2.8                                                                             ±1.3                                6     Δ%   -16%    -23%    -77%  -98%                                                    +36%    -44%    -67%  -98%                                   ______________________________________                                    

                  TABLE 6c                                                        ______________________________________                                        Mean whole-body uric acid concentrations (μg/mg dry                        tissue weight ±SEM), in three groups of German cockroaches                 offered untreated food (RC), or food treated with 1% xanthine                 (RCX) and 2% trimethoprim (w/w).                                              WEEK       GROUP     RC      RCX + 2% T                                       ______________________________________                                        3-4        males      2.04    2.61                                                                 ±0.12                                                                              ±0.05                                                              n = 19  n = 9                                                       females    2.54    2.64                                                                 ±0.06                                                                              ±0.03                                                              n = 17  n = 3                                                       nymphs     2.76    2.62                                                                         ±0.12                                                              n = 1   n = 9                                            ______________________________________                                    

EXAMPLE 9 Treatment of Resistant Cockroaches with Xanthine-OxypurinolCompositions

Colonies of cockroaches were prepared as previously described, exceptthat the insects were taken from laboratory stocks of two Germancockroach strains that are known to be resistant to insecticidescommonly used for cockroach control. The two strains were: (A) theHawthorne strain, and (B) the Las Palms strain. Profiles of theresistance ratios exhibited by these two strains are shown in Table 7abelow.

                  TABLE 7a                                                        ______________________________________                                        Resistance ratio (RR) profiles for the Hawthorne and                          Las Palms resistant strains, where, on a continuum of rising                  resistance, RR >2.0 indicates that resistance is developing,                  and RR ≧3.0 indicates that the gene frequency for resistance           has increased. RR is calculated as (Test strain LT.sub.50) ÷              (Susceptible strain LT.sub.50), where LT.sub.50 is the time it takes for      the intoxicant to achieve 50% mortality in a treated                          population                                                                    INSECTICIDE      HAWTHORNE   LAS PALMS                                        ______________________________________                                        ORGANOPHOSPHATES RR                                                           Diazinon         2.0         >75                                              Chloropyrifos    10.8        >50                                              Acephate         2.0         1.2                                              Malathion        5.5         >50                                              CARBAMATES                                                                    Propoxur         1.7         >60                                              Bendiocarb       2.2         >70                                              PYRETHROIDS                                                                   Pyrethrins       >140        >140                                             Allethrin        >140        >140                                             Permethrin       0.5         3.2                                              Phenothrin       0.6         >120                                             Fenvalerate      0.9         >60                                              Esfenvalerate    0.8         7.0                                              Cyfluthrin       1.8         2.5                                              Cypermethrin     1.6         >80                                              BIO-CHEMICAL                                                                  Avermectin       2.4         1.5                                              ______________________________________                                    

Individual consumption (ICmg) in the first three-weeks was calculated aspreviously described. As shown in Tables 7b and 7c below, ICmg for bothstrains was consistent across all concentrations of the food mixtures.The Hawthorne strain exhibited a maximum decrease in consumption of 22%for a diet containing 3% oxypurinol. This represents a dose of 1,260 μgof oxypurinol over the first three weeks.

                  TABLE 7b                                                        ______________________________________                                        Mean individual consumption (ICmg), over time (wks)                           of rodent chow offered without (RC), or with 1% xanthine (RCX),               and with various concentrations (w/w) of oxypurinol (OXY %), by               German cockroaches of the Hawthorne and Las Palms resistant                   strains.                                                                      TIME    RCX + OXY %                                                           (wks)   RC        0.1     1.0     2.0   3.0                                   ______________________________________                                        HAWTHORNE STRAIN                                                              3       53.6      47.1    48.0    47.1  42.0                                          (±3.5) (±0.6)                                                                             (±1.3)                                                                             (±0.5)                                                                           (±0.4)                                     n = 4     n = 3   n = 3   n = 3 n = 4                                 LAS PALMS STRAIN                                                              3       45.2      39.5    40.0    40.0  40.3                                          (±1.3) (±1.0)                                                                             (±0.4)                                                                             (±2.3)                                                                           (±0.5)                                     n = 4.    n = 3.  n = 3   n = 3 n = 4                                 ______________________________________                                    

The effect of xanthine-oxypurinol combinations on population growth wasdetermined as previously described. As shown in Tables 7c and.7d below,the combination controlled the population growth of both resistantstrains.

                  TABLE 7c                                                        ______________________________________                                        Percent changes (+ or -) in mean population number in                         colonies of German cockroaches of the Hawthorne resistant                     strain, offered food without (RC) or with 1% xanthine (RCX),                  and with various concentrations (w/w) of oxypurinol (OXY %),                  over time (weeks). n = 3.                                                     TIME                RCX + OXY %                                               wks     RC          0.1    1.0    2.0  3.0                                    ______________________________________                                        6       +438%       -32%   -22%   +12% -21%                                   9       +997%       -55%   -59%   -38% -67%                                   12      +1,601%     -77%   -78%   -76%                                        ______________________________________                                    

                  TABLE 7d                                                        ______________________________________                                        Percent changes (+ or -) in mean population number in                         colonies of German cockroaches of the Las Palms resistant                     strain, offered food without (RC) or with 1% xanthine (RCX),                  and with various concentrations (w/w) of oxypurinol, over time                (weeks). n = 3.                                                               TIME                RCX + OXY %                                               wks     RC          0.1    1.0    2.0  3.0                                    ______________________________________                                        6        +146%      +50%   +68%   +31% -25%                                   9       +1,074%     -50%    -8%   -60% -70%                                   12      +1,624%     -78%   -67%   -88% -95%                                   ______________________________________                                    

EXAMPLE 10 Treatment of Resistant Cockroaches with Xanthine-TrimethoprimCompositions

Colonies of cockroaches were prepared as described, using the Hawthorneand Las Palms resistant strains.

As shown in Table 8a below, for the Hawthorne strain, feeding wasinhibited in relation to the control, in direct ratio to theconcentration of trimethoprim in the diet. The maximum decrease of 62%occurred at 4.0% T concentration, which represents a dose of 639 μg oftrimethoprim per individual over the first three weeks. Populationgrowth of the Hawthorne strain was controlled at the higherconcentrations.

                                      TABLE 8a                                    __________________________________________________________________________    Mean individual consumption (ICmg), and percent                               change (Δ%) in mean population numbers, in colonies of German           cockroaches of the Hawthdrne resistant strain offered food                    without (RC), or with 1% xanthine (RCX), and various                          concentrations (w/w) of trimethoprim (T %) over time (weeks).                 TIME      RCX + T %                                                           (wks)                                                                             TEST  RC  0.5  1.0 2.0  3.0 4.0                                           __________________________________________________________________________    3   ICmg  42.5                                                                              37.6 37.1                                                                              30.4 17.2                                                                              15.9                                              (±SEM)                                                                           (±0.7)                                                                         (±2.1)                                                                          (±1.7)                                                                         (±2.0)                                                                          (±1.2)                                                                         (±1.4)                                               n = 7                                                                             n = 3                                                                              n = 3                                                                             n = 6                                                                              n = 6                                                                             n = 3                                         3   Δ%                                                                            -7% -2%  -6% -27% -7S%                                                                              -79%                                                    n = 7                                                                             n = 3                                                                              n = 3                                                                             n = 6                                                                              n = 4                                                                             n = 3                                         6   Δ%                                                                            +368%        -70% -79%                                                                              -89%                                                    n = 4        n = 3                                                                              n = 4                                                                             n = 3                                         9   Δ%                                                                            +606%                                                                             +369%                                                                              +298%                                                                             -17% -95%                                                                              -94%                                                    n = 7                                                                             n = 3                                                                              n = 3                                                                             n = 6                                                                              n = 4                                                                             n = 3                                         12  Δ%                                                                            +913%        -51% -93%                                                                              -97%                                                    n = 3        n = 3                                                                              n = 3                                                                             n = 3                                         __________________________________________________________________________

For the Las Palms strain, as shown in Table 8b below, an even decline inICmg of treated food occurred in direct relation to the increase inconcentration of trimethoprim. The maximum inhibition, compared with thecontrol, was 38% at 6% T concentration which constitutes an ingesteddose of 1,758 μg of trimethoprim per individual over three weeks.Population numbers were reduced by two-thirds at six weeks of treatment.

                  TABLE 8b                                                        ______________________________________                                        Mean individual consumption (ICmg) and percent change                         (Δ%) in mean population number, in colonies of German                   cockroaches of the Las Palins resistant strain offered food                   without (RC), or without 1% xanthine (RCX), and with various                  concentrations (w/w) of trimethoprim (T%) over time (weeks).                  n = 3                                                                         TIME                RCX + T%                                                  (wks)  TEST    RC       3.0   4.0   5.0   6.0                                 ______________________________________                                        3      ICmg    47.0     43.0  41.3  37.0  29.3                                       (±SEM)                                                                             (±3.8)                                                                              (±3.5)                                                                           (±2.2)                                                                           (±2.3)                                                                           (±1.8)                           3      Δ%                                                                               -12%     -24% -26%  -43%  -57%                                6      Δ%                                                                              +336%    +100% -37%  -37%  -67%                                ______________________________________                                    

EXAMPLE 11 Treatment of Cockroaches withXanthine-Oxypurinol-Trimethoprim Compositions

Colonies of German cockroaches of the VPI susceptible strain andcolonies of the Hawthorne resistant strain were offered either untreatedrat chow (RC), or rat chow treated (w/w) with 1% xanthine (RCX),combined with 2% oxypurinol (OXY) and 2% trimethoprim (T). Individualconsumption and changes in colony populations results are shown inTables 9a (VPI strain) and 9b (Hawthorne strain). In both, colonies werevirtually extinct by six weeks of treatment, in spite of declines inICmg of ≧50%.

                  TABLE 9a                                                        ______________________________________                                        Mean individual consumption (ICmg) and percent change                         (Δ%) in mean population number in colonies of German                    cockroaches of the VPI susceptible strain offered food without                (RC) or with 1% xanthine (RCX) and with 2% oxypurinol (OXY)                   and 2% trimethoprim(T) (w/w), over time (weeks).                              TIME               RC      RCX + 2% OXY + 2% T                                (wks)   TEST       n = 1   n = 3                                              ______________________________________                                        3       ICmg       71.3    34.9                                                       (±SEM)          (+1.6)                                             3       Δ%    -5%    -68%                                               6       Δ%   +955%   -99%                                               ______________________________________                                    

                  TABLE 9b                                                        ______________________________________                                        Mean individual consumption (ICmg), and percent                               change (Δ%) in mean population number in colonies of German             cockroaches of the Hawthorne resistant strain offered food                    with (RC), or with 1% xanthine (RCX) and with 2% oxypurinol                   (OXY) and 2% trimethoprim (T) (w/w), over time (weeks).                       TIME               RC      RCX + 2% OXY + 2% T                                (wks)   TEST       n = 1   n = 3                                              ______________________________________                                        3       ICmg       72      34.1                                                       (±SEM)          (±0.6)                                          3       Δ%   -2.4%   -16%                                               6       Δ%   +1416%  -98%                                               ______________________________________                                    

EXAMPLE 12 Assessment of Purines with Oxypurinol or Trimethoprim

Colonies of cockroaches of the VPI susceptible strain were prepared aspreviously described. The diets offered were rat chow alone (RC), ratchow (w/w) with it xanthine and 3% trimethoprim (RCX+T), rat chow withit hypoxanthine and 3% trimethoprim (HX+T), rat chow with 1% guanine and3% trimethoprim (G+T), and rat chow with 1% hypoxanthine and 1%oxypurinol (HX+OXY). Individual consumption (ICmg), and change inpopulation numbers were calculated as before, with the results shown inTable 10, below.

The results, with hypoxanthine and guanine replacing the xanthinecomponent of the diet mixtures, compared closely with those obtainedwith xanthine. This was the case with both trimethoprim and oxypurinol,with population growth being controlled to extinction of the colonies.Some feeding inhibition occurred in all of the trimethoprim mixtures.

                  TABLE 10                                                        ______________________________________                                        Mean individual consumption (ICmg), and percent                               change (Δ%) in mean population numbers, in colonies of German           cockroaches of the VPI susceptible strain offered food without                (RC), or with 1% of a purine (w/w) and either 3% trimethoprim                 (T), or 1% oxypurinol (OXY), over time (weeks). Purines were                  xanthine (X), hypoxanthine (HX), or guanine (G).                              TIME          RC      RCX + T                                                                              HX + T                                                                              G + T HX + OXY                             (wks) TEST    n = 2   n = 2  n = 2 n = 2 n = 1                                ______________________________________                                        3     ICmg    54      26     25    29    42                                         (tSEM)  (±0) (±8.0)                                                                            (±1.0)                                                                           (±8.0)                                  3     Δ%                                                                              -5.5    -68    -74   -71   -17                                  6     Δ%                                                                               +152   -99    -91   -94   -83                                  9     Δ%                                                                              +1426   -100   -100  -100  -100                                 ______________________________________                                    

We claim:
 1. A composition for controlling an insect pest whichsalvages, stores, or excretes its nitrogenous wastes via the purinemetabolic pathway, comprising a purine selected from the groupconsisting of xanthine, hypoxanthine, guanine, and mixtures thereof, inan amount of about 1.0%, by weight, and a dihydrofolate reductaseinhibitor selected from the group consisting of trimethoprim,methotrexate, and mixtures thereof, in an amount of about 0.1% to about6.0%, by weight.
 2. A composition according to claim 1, wherein thepurine is xanthine, in an amount of about 1%, by weight, and thedihydrofolate reductase inhibitor is trimethoprim, in an amount of about0.1% to about 6.0%, by weight.
 3. A composition according to claim 2,wherein the trimethoprim is present in an amount of about 0.1%, byweight.
 4. A composition according to claim 2, wherein the trimethoprimis present in an amount of about 0.5%, by weight.
 5. A compositionaccording to claim 2, wherein the trimethoprim is present in an amountof about 1.0%, by weight.
 6. A composition according to claim 2, whereinthe trimethoprim is present in an amount of about 2.0%, by weight.
 7. Acomposition according to claim 2, wherein the trimethoprim is present inan amount of about 3.0%, by weight.
 8. A composition according to claim2, wherein the trimethoprim is present in an amount of about 4.0%, byweight.
 9. A composition according to claim 2, wherein the trimethoprimis present in an amount of about 5.0%, by weight.
 10. A compositionaccording to claim 2, wherein the trimethoprim is present in an amountof about 6.0%, by weight.
 11. A composition according to claim 1,wherein the purine is hypoxanthine, in an amount of about 1.0%, byweight, and the dihydrofolate reductase inhibitor is trimethoprim, in anamount of about 0.1% to about 6.0%, by weight.
 12. A compositionaccording to claim 11, wherein the trimethoprim is present in an amountof about 3.0%, by weight.
 13. A composition according to claim 1,wherein the purine is guanine, in an amount of about 1.0%, by weight,and the dihydrofolate reductase inhibitor is trimethoprim, an amount ofabout 0.1% to about 6.0%, by weight.
 14. A composition according toclaim 13, wherein the trimethoprim is present in an amount of about3.0%, by weight.
 15. A method of controlling an insect pest whichsalvages, stores, or excretes its nitrogenous wastes via the purinemetabolic pathway, which comprises bringing into contact with said pest,a growth-controlling amount of a composition comprising a purineselected from the group consisting of xanthine, hypoxanthine, guanine,and mixtures thereof, in an amount of about 1.0%, by weight, and adihydrofolate reductase inhibitor selected from the group consisting oftrimethoprim, methotrexate, and mixtures thereof, in an amount of about0.1% to about 6.0%, by weight.
 16. A method according to claim 1,wherein the insect is a cockroach.
 17. A method according to claim 1,wherein the purine is xanthine, in an amount of about 1.0%, by weight,and the dihydrofolate reductase inhibitor is trimethoprim, in an amountof about 0.1% to about 6.0%, by weight.
 18. A method according to claim17, wherein the trimethoprim is present in an amount of about 0.1%, byweight.
 19. A method according to claim 17, wherein the trimethoprim ispresent in an amount of about 0.5%, by weight.
 20. A method according toclaim 17, wherein the trimethoprim is present in an amount of about1.0%, by weight.
 21. A method according to claim 17, wherein thetrimethoprim is present in an amount of about 2.0%, by weight.
 22. Amethod according to claim 17, wherein the trimethoprim is present in anamount of about 3.0%, by weight.
 23. A method according to claim 17,wherein the trimethoprim is present in an amount of about 4.0%, byweight.
 24. A method according to claim 17, wherein the trimethoprim ispresent in an amount of about 5.0%, by weight.
 25. A method according toclaim 17, wherein the trimethoprim is present in an amount of about6.0%, by weight.
 26. A method according to claim 15, wherein the purineis hypoxanthine, in an amount of about 1.0%, by weight, and thedihydrofolate reductase inhibitor is trimethoprim, in an amount of about0.1% to about 6.0%, by weight.
 27. A method according to claim 26,wherein the trimethoprim is present in an amount of about 3.0%, byweight.
 28. A method according to claim 15, wherein the purine isguanine, in an amount of about 1.0%, by weight, and the dihydrofolatereductase inhibitor is trimethoprim, an amount of about 0.1% to about6.0%, by weight.
 29. A method according to claim 28, wherein thetrimethoprim is present in an amount of about 3.0%, by weight.
 30. Themethod according to claim 15, wherein said composition is administeredby incorporation into a bait or attractant for pest insects which isingested by said pest insects.